3,22-diacyloxy-5,7,9 (11), 20(22)-bisnorcholatetraenes



to a process tor he pr application is a con inuation in bi no cnolatetra nes Qther objects 9 a o s ro m ound aving an. esteem Patented Dec. 11, 1951 cbrpoiatiipii of Michigan 1 s Gianna. (c1. ago-39 1.5)

The present invention relates t9 fizg-diacyi- 3y 5,7,9 11 20(22) W11 i. 9 .9 9 1 {p if pricrrfiled pe in pli t'p fie iel flli fia filed January 3, 1950,

The unds f th prese t i 9. 2 may he re e ted by he immer! i9 5. I

9H9 31:01:10 Ac wherein Ac is the residue of an organic .carhoxylic acid containing from. one to ei h car nn stems. inclusive. q

It is an obiectcoi th present intention topmitid a novel roup of c mp unds whicharerusefyl in t pr pa at on o ste oid. aomnounsl ant i ox e t m at. .carbon a m e ven- Another obje t of h ve ti n s t e. proyisigp o a r e s fo the-prodimt oniof inQYfil cam yention will become apparent h r ina ter; Th c p u s of t e resent inve ii n. a rev u y stated a useiu n he rep atien attac d to carbo .at leyenfinch coinp unds are o ular in ere t he. ield of ste o d r s ch due to he ;bio1 o a1 :.aetirity 9 h cort c h rmones and certain zls oc nzdea ve of. w h emana ed-steroids ar kno n to h v bio q oal t e is i iif. m a ed yi th m rtesn at dste o v I i-is.

th fpr o mn tan o in e ti at the ox en te der vat ve oi such steroiqsnarticula t e'oxy h d a car o atom el ven. a w as to .i pwe t ate the b o o ical activity of the unoxygenated compounds and their transformation products. The importance of'such investigation is: moreover emphasized by the acute shortage of adrenal cortical hormones, and

the absence of .any present suggestion for aileviationof the said shortage except through organic synthesis, J

Novel compounds ot "the present inyentip n wh ar 9 pa ti i ierfi are i 9 "9955*- 7 B E' QBQH PAFETME ES A Vern 'MQ M Sh J!" 52 as'si'gnorg johfi' eoinpansi neiama gari n anim fientsigber .9 9. 13?! M 5%?! pounds of the above generic formula wherein represents an ester of the 3-hydroxy group "withacarhoxyiic "acid containing u to and ineluding eightgarbonato s. Among the acids 22:21.1, of the formula:

which can be used areformic,acetic, propicnic, but ic, Valerie. hexanoic, he ptanoic; ec'tanoic, succuiic, fglutaric, eycloperitanoic, cycloheganoic, 'bi z'c iij'c; "tame, "and the like. 7 Maine iower' aiiphatic acids; The acids may also containsubstituents,such as halo; alky-l. and methoky, 'w'mcnare "non-reactive under the reaction conditionsefnployed.

'Ihe' compounds 'of the present invention are prpa'rea by the removal 'of the maleic anhyg iricle 'i'adilca'l f rm a 3,22'-diacyioxy-5,7,9 (-11) .20 22) tieii heia aa aqs t ifih rm ia tea e wherein A iepresents the adduct radical of maleic ,flnhydridm and A; has the yalue p eviously assi ned.

511 11 322 diacyloxywfii'kfitl 1:) ,;2 .0.(..22) :hisnor .cholatetraene adducts fl[;22.-.eno1 esters of .8zaoyl- Qxybisn r=5.'7,9 (11),=ch91atriene 22 al addncts] are conveniently p epared by su jecting an addu tofa;3:acyloxy isnorzfiflfifii1').-cho1atrien I CH:

" eam Preferred acids claimed in the copending application Serial range are readily obtained by cooling the solution 111,100 of Robert H. Levin, filed August 18, 1949, of the adduct with a bath of solid carbon dioxide and as more fully described hereinafter. in acetone or the like, although various other The 3=esters of dehydroergosterol, from which methods of cooling can be used. Many of the the 3-acyloxy=bisnor-5,7,9(ll) cholatrien-22-al 5 customary solvents used in ozonizations such as adducts are prepared, can be synthesized in 'sevchloroform, acetic acid, carbon tetrachloride, eral ways starting With ergosterol. For example, ethylene chloride, methylene chloride, and the ergosterol can be transformed to dehydroergos- H like, can be used.

terol with mercuric acetate according to known f -The 'ozonides are then decomposed under remethods [Windaus et al., Ann. 465,157 (1928)]' 6- ducin'g conditions, that is, in the absence of and the 3-hydroxy group -.of. the dehydroergosoxidizing agents, whether added or formed in terol acylated by known; procedure-ZiAlt'erna-E the'course of the reaction by products of detively the 3-hydroxy group oflergosteroli canbe "composition of the ozonide. This means that acylated prior to the preparation of the dehydro excess oxy en formed by decomposition of the derivative, a procedure which is pa 'ticularly ozonide is prevented from forming hydrogen preferred in the preparation of the '3-acetoxy peroxide by combining with any moisture present, derivative. The adducts of dehydroergosterol and that molecular oxygen is prevented from are then prepared by the addition of maleic an-,- oxidizing the aldehyde thus formed. This can hydride or the like to dehydroergosterol or a 3- be conveniently accomplished by decomposing ;ester'- thereof according to .known methods the ozonide in glacial acetic acid by the addition [Honigmann, .Ann. 508, 89 (1934)]. .The anof finely-powdered zinc.

.hydrides can then be converted to their correas is conventional with ozonizations when con- :sponding acids and esters if desired. ducted in solvents, other than glacial acetic acid,

The ester group, when present in the 3-posithe solvent used for ozonization is replaced, afttion'of dehydroergosterol, is for thepurpose of 2;; er completion of the ozonization, by adding protecting the 3-hydroxy group. in subsequent glacial acetic acid and removing the lower-boilchemical reactions. For this purpose any coning solventby fractional distillation. Alternavenient ester of anorganic carboxylic acid, which tively, the solvent can be removed by careful non-reactive under the conditions of the reacwarming under reduced pressure prior to the tion, issuitable. The preferred acids are the addition of glacial acetic acid, if desired.

fatty acids such as formic, acetic, propionic, After decomposition of the ozonide and re- ;butyric, valeric, hexanoic, heptanoic, octanoic; moval of the zinc, the aldehyde can be recovered dibasic acids such as malonic, succinic, phthalic; by diluting the acetic acid with water, or in other cycloa-liphatic acids suchas cyclopentanoic and conventional manner, such as by formation of cyclohexanoic; and aromatic acids ,such as an aldehyde derivative, e. g., the dinitrophenylbenzoic, toluic, andthe like. The acids may also hydrazone. contain substituents such as halogen, alkyl, the Adducts of 3,22-diacyloxybisnor-5,7,9(11),- methoxy radical, and the like, and these sub- 20(22)-cholatetraenes [22-enol esters of adducts stituents willbe carriedthroughout the syn-, of 3 acyloxybisnor'-5,7,9(1l)-cholatrien-22-a1s] thesis. If desired, the acylgroup can be changed 40 canb'e conveniently prepared by heating the to another acyl group by'saponifying the ester to corresponding 3-hydroxy or S-acyloxy aldehyde give a 3-hydroxy compound, which can then be maleic acid, maleic acid anhdyride, or maleic re-esterified as previously described. acid'ester adduct witha large excess of an or- A preferred method for preparing some of the ganic carboxylic acid anhydride in the presence dehydroergosteryl adducts comprises the saponi- 15f a small-amount of the alkali metal salt of fication of 3-acyloxy-adductoLdehydroergosterthe: acid corresponding to the anhydride emol with dilute alkali followed by acidification. ployed or an acid catalyst such as para-tolu- The 3 h ydroxy dicarboxylic acidfth'us 'formed -e'ne sulfonic or sulfuric acid. The preferred an- 'Jcan be converted to the 3-hydroxy an'hydride-by.. "hydride is acetic. anhydride, but other anhyheat, or it can be converted to any desired 3- '-drides, 1 such as propionic, butyric, valeric,

" a'cyloxy anhydride adduct by heating under hexanoic, and octanoic anhydrides, as Well as "reflux with the appropriate acid' anhydride or benzoi'c acid anhydride, ortho-toluic acid anhychloride in pyridine solution" Dialkyl esters of --'dride,' and the like, are also operative. The acid the previously mentioned'dicarboxylic acid adanhydrides can also be substituted by non-reacducts can be prepared by subjecting the acid to the groups, such as halo, alkyl, and methoxy, the action of an esterification reagent suchasa as in the case of chloroacetic, ortho-toluic, or diazoalkane [Wilds et al., J. Org. Chem. 13, 763 methoxybenzoicaci'd anhydrides. The reaction (1948)], e. g., diazomethane, diazoethane, diazo -can be conveniently followed by observing the butane, and the like. color changes in the reaction mixture, optimum The selective 'oxidationof an adduct of dehy- .yields being obtainedby discontinuing the applidroergosterol, orwa 3-,ester thereof, to produce an cation of heat when the color of the solution adduct of 3hydroxybisnor-5,7,9(l1)-cholatrien- *changes from yellow to brown. Ordinarily the 22-al, Or a 3-8813; there s a o p e y disreaction is heated at about 140 degrees centigrade solving the dehydroergostery'l' adduct in a suit- .forfrom about four to six hours, but temperaable solvent, cooling to about minus 80 to plus tures as low as 100 and as high as 180 degrees 30 degrees centigrade, and passing ozone into w centigrade are also operative. The reaction is the solution until about'LO to. 1'.25 moles of ozone gusually conducted at the boiling point of the anper-.mc of adduct h b absorbed, h hydride'but in the case of the higher-boiling antemperature of the solution should be maintained... hydrides, ch as benzoic anhydride, a suitable J W'DI 30 degrees ent e r eyo temperature control, such as 100-150 degrees degrees centigrade, during the'addit'ion of; ozone,

w en a temperature of minus nd min s centigra de, must be used, since the adduct otherwise tends to decompose in the higher. temperaalthoughtemperatures' as 0mg; m miSliD-aQdaS .--ture range. If a 3-hydroxy, aldehyde adduct is lllgIifiS 'p'lus degrees centig jrade, are opera-g thus-reactedwith an anhydride, the hydroxy 'tive. The lower temperatures of the preferred group will be acylated, and, similarly, if a maleic acid adduct is used instead of -'a diest'er or an anhydride, the anhydride will be formed. The enol ester can be isolated by removing the excess anhydride under reduced pressure, and separating the enol ester from alkali metal salts, which procedure yields a product sufliciently pure for most purposes, but which can be further purified by recrystallization from acetone-water, acetonepentane, or like solvents, if desired.

The method of the invention consists in heating a 3,22 diacyloxy 5,7,9(11),20(22) bisnorcholatetraene maleic anhydride adduct in the presence of an organic amine at a temperature of about 100 to 225 degrees centigrade, with or without the presence of an organic solvent, and thereafter isolating the product. The method of the invention has the advantage of being conveniently applicable to large scale work in that it is vnot necessary to remove the components from the reaction mixture to complete the reaction. It also has the further advantage that the -desiredtetraene can be obtained in a high degree of purity and in excellent yields.

Amines that can be used in the process of the invention are: secondary aliphatic amines such as dimethylamine, diethylamine, dipropylamine, dibutylamine, diamylamine, dioctylamine; tertiary aliphatic amines such as trimethylamine, triethylamine, triamylamine, methyldioctylamine;methyldiethylamine; secondary and tertiary cyc'loaliphaticamines, such as N-methylcyclohexylamine, N,N dimethylcyclohexylamine, N,N-diethylcyclohexylamine.; secondary and tertiary heterocyclic amines such as ,pyrrolidine, N- m'ethylmorpholine, N-ethylpyrrolidine morpho- "l-ine, piperidine, 'N methylpiperidine, 2-methylpiperidine, 1,2 dimethylpiperidine, 1,2,4 trimethylpiperidine, 2,4,6 trimethylpiperidine, 1- ethyl 2,4,6-trimethylpiperidine; aromatic heterocyclic amines such "as pyridine, ,picoline,

lutidine, collidine, quinoline, quinaldine, lepidine, 3-methylquinoline; secondary and tertiary carbocyclic aromatic amines such as 'N-meth'yl aniline, N-ethylariiline, N butylaniline, N benzylaniline, N,N-dimethylaniline, N ,N-diethylaniline, N,N-dibutylaniline, N, N dibenzylani'l'ine, N- methyltoluidine, N,N diethyltoluidine, N -ethyl- ,xylidine, N,N dimethylaminoethanol, dibutylethanol; substituted aromatic amines such as ortho-methoxy N,N dimethylaniline, para- -ethoxy N,N-diethylaniline, parachloro-N,N-dimethylaniline, para-bromo-N,N diethylaniline, para-fluoro N,N-dibutylaniline, N,N-dimethylmesidine; secondary and tertiary aralkyl amines such as methylbenzylamine, dimethylbenzylamine, propylbenzylamine, diisopropylphenethylamine, diethylphenylisopropylamine; and primary amines such asbutylamine, hexylamine, octylamine, cyclohexylamine, aniline, toluidine, xylidine and the like.

- The process of the present invention, then, comprises heating a selected 3,22-diacyloxy- 5,7,9(11) ,20 (22) -bisnorchloatetraene maleic anhydride adduct to a temperature between about 100 and 225 degrees centigrade, preferably between about 175 and 200 degrees centigrade, in the presence of an organic amine, removing excess amine, and recovering the product, wherein the maleic anhydride adduct has been eliminated from the molecule, with production of the conjugated double bond system at carbon atoms 5,6:7,'8. The time required for the reaction is usually from about one toeight hours, dependfin'g upon variable factors such' as the particular Vaminoethanol, N-pyrrol'idylethanol, N-p'iperidylsteroid adduct treated, the amine employed, and the temperature of reaction. Ordinarily, a reaction period of about four hours is entirely satisfactory, although, at the lower temperatures, a more extended period may be employed to advantage. The employment of pressure may in some cases be advantageous, although it is in most cases preferred to conduct the pyrolysis reaction at atmospheric pressure.

The following examples are illustrative of the process and products of the present invention, but are not to be construed as limiting.

Preparation 1.-Dimethyl ma'leate adduct of dehydroergosteryl benzoat'e To a solution of '21 grams of dimethyl maleate adduct of dehydroergosterol in 69 milliliters of warm pyridine was added 9.5 milliliters of benzoyl chloride. After standing at room temperature for fifteen minutes, the mixture was poured into 1400 milliliters of ice-water and the solid removed by filtration, dried, and recrystallized from acetone. There was thus obtained 26.4 grams of dimethyl maleate adduct of dehydroergosteryl benzoate, melting at 203 to 205.5 degrees centigrade.

Preparation 2.--Dimethyl malea'te adduct of dehydroergosteryl acetate In I a manner essentially that described in Preparation 1, the dimethyl maleate adduct of dehydroergosteryl acetate, melting at 177 to 179 degrees centigrade, was prepared from the dimethyl maleate adduct of dehydroergosterol and acetyl chloride.

Preparation 3.-Dimethyl maleate adduct of dehydroergosteryl formate A solution of six grams of dimethyl maleate adduct of dehydroergosterol in fifty milliliters of 87 percent formic acid was heated under reflux for one hour, cooled, and the dimethyl maleate adduct of dehydroergosteryl formate filtered therefrom. Upon crystallization from acetone, the purified material melted at 177.5 to 178.5 degrees centigrade.

Preparation i.-Maleic acid'adduct of dehydroergosterol c'entigrade.

Preparation 5.Maleic anhydride adduct of 3-heptanoyZoxydehgI droergosterol The maleic acid adduct of dehydroergosterol from Preparation 4 was dissolved in a mixture of seven milliliters of warm pyridine and fourteen milliliters of heptylic anhydride, and the mixture heated under reflux for one hour. About eighty percent of the reaction solvent was removed under reduced pressure, and the residue then dissolved in methyl alcohol. The methyl alcohol solution'was concentrated and cooled to yield 4.8 grams- 015 the maleic 'anhydride adduct 10f 3 heptanoyloxydehydroergosterol; melting at 186- 191.5 degrees centigrade.

Preparation 6.-Maleic anhydride adduct 3 beta-acetozcybz'snor 5,7,9, (11) cholatrien- 22-111 A solution of 5.35 grams of the maleic anhydride adduct of 3-beta-acetoxydehydroergosterol in 107 milliliters of methylene chloride was cooled to about minus seventy degrees centigrade and ozonized until 505 milligrams of ozone had been absorbed. The temperature of the solution was then gradually raised to about plus ten to fifteen degrees centigrade, whereupon seventy milliliters of glacial acetic acid was added and the methylene chloride removed under reduced-pressure. Seven grams of zinc dust was then added to the cold solution at a uniform rate over a period of ten minutes, while keeping the reaction temperature below plus twenty degrees centigrade. After being stirred for fifteen minutes, the mixture was filtered and the filtrate poured into water. There was thus obtained 4.31 grams of maleic anhydride adduct of 3-beta-acetoxybisnor-5,7,9(11)- cholatrien-22-al, a fine white powder which melted at 187-197 degrees centigrade.

To a solution of 0.30 gram of the maleic anhydride adduct of 3-beta-acetoxybisnor-5,7,9(ll)- cholatrien-22-al, in thirty milliliters of ethanol, was added twenty milliliters of alcohol containing one percent 2,4-dinitrophenylhydrazine and three percent concentrated hydrochloric acid. The mixture was allowed to stand for'one hour at room temperature and then placed in a refrigerator to complete precipitation of the yellow crystals. The precipitate was then collected and recrystallized from a mixture of chloroform and alcohol, to give the 2,4-dinitrophenylhydrazone of the maleic anhydride adduct of 3beta-acetoxybisnor-5,7,9(11) -cholatrien-22-al, melting at 269- 2'71 degrees centigrade.

Preparation 7.Malez'c anhydride adduct of 3- beta-acetomybisnor-i? ,9 (1 1) -choZatrien-22-al A two-liter, round-bottom flask was charged with fifty grams (0.93 mole) of dehydroergosteryl acetate maleic anhydride adduct and one liter of methylene chloride. The solution was cooled to Dry-Ice temperature with a trichloroethylene bath and ozonized oxygen passed through at a rate of 1200 milliliters of oxygen per minute (at this rate the ozonizer was producing about 86 milligrams of ozone per minute). The flow of ozonized oxygen was maintained for 128 minutes, a total of 4608 milligrams (105 percent) of ozone being passed into the solution. The reaction mixture was transferred to a two-liter, roundbottom flask fitted with a capillary and a condenser for downward distillation, 300 milliliters of acetic acid added, and the methylene chloride distilled over in vacuo at forty degrees centigrade or below. The flask was then placed in a water bath and fitted with a stirrer. An additional 200 milliters of acetic acid was added and the ozonide decomposed by the addition of fifty grams of zinc dust. The zinc dust was added in portions over a period of twenty to thirty minutes while the solution was stirred and the temperature maintained at seventeen to twenty degrees centigrade. Aftr addition, the mixture was stirred for another twenty minutes and then filtered. The precipitated zinc dust was washed by filtering 100 milliliters of acetic acid therethrough and the filtrate gradually diluted with Water (1100 to 1200-milliliters) until the product had been drowned out;

The product was .then cooled in the refrigerator overnight and filtered. The yield of crystalline product was 12 grams, assaying 89-95 percent of the desired aldehyde.

Preparation 8 in a manner essentially that described in Preparation 6, the following compounds were prepared.

(1) Maleic anhydride adduct of 3-beta-formoxybisnor-5,7,9 (11) -cholatrien-22-al, melting at -130 degrees centigrade. 2,4-dinitrophenylhydrazone, melting at -168 degrees centigrade.

(2) Maleic anhydride adduct of B-beta-heptanoyloxybisnor 5,7,9(11) cholatrien 22 a1, melting at 1975-1599 degrees centigrade. 2,4- dinitrophenylhydrazone, melting at 253-257 degrees centigrade.

(3) Dimethyl maleate adduct of 3-beta-ben- -zoyloxybisnor-5,7,9 (11) -cholatrien-22-al, melting at 183-187 degrees centigrade. 2,4-dinitrophenylhydrazone, melting at 224-249 degrees centigrade.

(4) Dimethyl maleate adduct of 3-beta-acetoxybisnor-5,7,9(l1) -cholatrien-22-al, melting at 172-178 degrees centigrade. 2-,4-dinitrophenylhydrazone, melting at 238 to 244 degrees centigrade.

(5) Dimethyl maleate adduct of 3-hydroxybisnor-5,7,9(l1) -cholatrien-22-al, melting at 163- degrees centigrade. 2,4-dinitrophenylhydrazone, melting at 250-254 degreescentigrade.

In a manner similar to the above, the maleic anhydride adduct of 3-hydroxybisnor-5,7,9(11)- cholatrien-22-al is obtained from dehydroergosteryl maleic anhydride adduct; the maleic acid adduct of 3-hydroxybisnor-5,7,9(11) -cholatrien- 22-al is obtained from dehydroergosteryl maleic acid adduct; and 3-acyloxybisnor-5,7,9(11) -cholatrien-22-al maleic acid adducts are obtained from the maleic acid adduct of 3-acyloxy-dehydroergosterols.

Preparation 9.-Dimethyl maleate adduct of 3- hydrorybisnor5,7,9 (11) -choZatrien-22-al A solution of 2.69 grams (.005 mole) of the dimethyl ester of the maleic acid adduct of dehydroergosterol, in eighty milliliters of methylene chloride, cooled by a Dry-Ice and trichloroethylene bath, was treated with ozonized oxygen until 247.36 milligrams (.0051 mole) of ozone was absorbed. The solution was then allowed to warm to room temperature, whereafter thirty milliliters of acetic acid was added and the methylene chloride removed in vacuo. While cooling in a water-bath at fifteen degrees centigrade, four grams of zinc dust was added in portions with stirring, the temperature being maintained between fifteen and twenty degrees centigrade. Stirring was continued for another fifteen minutes, whereafter the zinc was separated by filtration. The filtrate was diluted with Water to cloudiness, extracted with ether, the ether extract washed with sodium bicarbonate and then 'with water to neutrality, the solution then dried over sodium sulfate and evaporated to dryness in vacuo. The residue was crystallized from acetic acid and water, giving 1.92 grams (81.5 percent of the theoretical), melting point 91-97 degrees centigrade, which yielded a dinitrophenylhydrazone derivative in 72.5 percent yield, melting point 212-238 degrees centigrade. The aldehyde was recrystallized and found to have a purified ,melting point of 163-170 degrees centigrade,

while the dinitrophenylhydrazone derivative was aawme degrees oentigrade was attained.

{Preparation10.-MdZeic-anhydride adduct 3- -bet'a acetowy 22 acetomybispor 5,17,9(11'); 20(22)-ch0latetraene 'A mixture. of twenty grams of the maleic anhydride adduct of 3'-beta-acetoxybisnor-5,7,9- (1 -cholatrien-22-al, six grams of anhydrous sodium acetate, and 600 milliliters of acetic anhydride, was heated under reflux for six hours, whereafter volatile components were removed under reduced pressure. The resulting solid was digested with five fifty-milliliter portions of boiling acetone for five minutes each, and the extracts combined and diluted with 130 milliliters of water. There was thus obtained sixteen grams of the maleic anhydride adduct of B-beta-acetoxy-22-acetoxybisnor-5,7,9(11) 0 (22) cholatetraene, which melted at 186 to 193 degrees centigrade. Recrystallization of the crude product from a mixture of acetone and pentane raised the melting point to 200.5 to 202 degrees centigrade.

Preparation 11 In a manner essentially that described in Preparation 10, the following compounds were prepared:'

(1) The dimethyl maleate adduct of 3-betabenzoyloxy 22 acetoxybisnor 5,7,9(11),20- (22) -cholatetraene, which melted at 210 to 211 degrees centigrade.

(2) The dimethyl maleate adduct of 3-betaacetoxy 22 acetoxybisnor 5,7,9(11),20(22)- cholatetraene, which melted at 181 to 183 degrees centigrade.

In the same manner as given above, 22-acyloxy, e. g., formoxy, acetoxy, propionoxy, butyroxy, valeroxy, hexanoyloxy, heptanoyloxy, octanoyloxy, benzoyloxy, naphthoyloxy, and the like 3 acyloxybisnor 5,7,9(11),20(22) cholatetraene adducts, are obtained from the compounds of Preparations 6, 7, and 8. Such representative compounds include 3-formoxy-22-acetoxybisnor- 5,7,9(11),20(22) cholatetraene, 3 propionoxy- 22 acetoxybisnor 5,7,9(11),20(22) cholatetraene, 3,22-dipropionoxybisnor5,7,9 11) ,20 (22) cholatetraene, 3,22 dibenzoyloxybisnor 5,7,9- (ll),20(22) cholatetraene, 3,22 dibenzoyloxybisnor 5,7,9(11),20(22) cholatetraene, and 3 heptanoyloxy 22 octanoyloxybisnor 5,7,9- (l1),20(22) -eholatetraene adducts with maleic anhydride or maleic acid esters such as the dimethyl maleate, diethyl maleate, dipropyl maleate, diisopropyl maleate, dibutyl maleate, dioctyl maleate, dibenzyl maleate, and the like.

EXAMPLE.3 (BETA) 22-DIACETOXY-5,7,9 (11), 2O (22 -BISNORCHOLATETRAENE (a) DimethyZaniline.A solution of one gram of the maleic anhydride adduct of 3(beta),22- diacetoxy 5,7,9(11),20(22) bisnorcholatetraene in ten milliliters of dimethyl aniline was heated under reflux for five hours, and the excess amine removed under reduced pressure. Upon crystallization of the residue there was thus obtained 0.65 gram (80 percent of theory) of 3(beta),22 diacetoxy 5,7,9(11) ,20(22) bisnorcholatetraene, which melted at 108 to 121 degrees centigrade.

(b) N,N-dimethylben2ylamine.-A solution of one gram of the maleic anhydride adduct of 3(beta) ,22 diacetoxy 5,7,9(11) ,20(22) bisnorcholatetraene in ten milliliters of N,N-dimethy1- benzylamine was heated under reflux for four --hours',-and the; excess amine removed: under reduced pressure. The residue. was dissolved in fifty milliliters of ethyl ether, washed with an equal volume of cold one percentpsuliuric acid,

'cold' five percent sodium. carbonate solution, water, an'didried. Upon removal of'the solvent ."by distillation and crystallization .of theresidue from methanol, therewas'obtained 0.73-r1gram of 3(beta) ,22 diacetoxy 5,7,9 (11) ,20(22) bisnorcholatetraene, which melted at 112m 122 degrees centigrade.

(c) Nethylpyrrolidine.--A solution of one gram of the maleic anhydride adduct of 3(beta) 22 diacetoxy 5,7,9(11) ,20(22) bisnor cholatetraene in ten milliliters of N-ethylpyrrolidine Was heated in an autoclave at 175 degrees centigrade for four hours, cooled, and the excess amine removed by distillation under reduced pressure. The residue was dissolved in milliliters of ethyl ether, washed with equal volumes of cold one percent sulfuric acid, cold five percent sodium carbonate solution, water, and dried. The solvent was removed by distillation and the residue dissolved in 100 milliliters of benzene and chromatographed over alumina. There was thus obtained 0.69 gram of 3(beta),22-diacetoxy-5,7,9(l1) ,20- (22) -bisnorcholatetraene, which melted at 108 to 121 degrees centigrade.

(d) M 0rphoZine.A solution of one gram of the maleic anhydride adduct of 3(beta) ,22-diacetoxy 5,7,9(11),20(22) bisnorcholatetraene in ten milliliters of morpholine was heated in an autoclave at 175 degrees centigrade for four hours, cooled, and the excess amine removed by distillation under reduced pressure. The residue was dissolved in 100 milliliters of ethyl ether, washed with equal volumes of cold one percent sulfuric acid, cold five percent sodium carbonate solution, water, and dried. The solvent was removed by distillation and the residue dissolved in 100 milliliters of benzene and chromatographed over alumina. There was thus obtained 0.15 gram of 3(beta) ,22 diacetoxy 5,7,9(11) ,20(22) bisnorcholatetraene, which melted at to 122 degrees centigrade.

In a manner similar to the above there can be obtained from the corresponding 3,22-diacyloxy- 5,7,9 (11) ,20 (22) -bisnorcholatetraene maleic anhydride adducts, 3-formoxy-, 3-propionoxy-, 3-

butyroxy-, 3-isobutyroxy-, 3-valeroyloxy-, 3- hexanoyloxy-, 3-heptanoyloxy-, and 3-octanoyloxy-22-acetoxy 5,7,9(11) ,20(22) bisnorcholatetraenes, 3-benzoyloxy-22-acetoxyor propionoxy- 5,7,9(11) ,20(22) -bisnorcholatetraene, 3-acetoxy- 22 propionoxy 5,7,9(11 ,20(22) bisnorcholatetraene, 3 propionoxy 22 butyroxy-5,7,9(11),- 20(22) bisnorcholatetraene, 3-butyroxy-22-octanoyloxy-5,7 ,9(11) ,20(22) bisnorcholatetraene, 3-butyroxy-22-benzoyloxy 5,7,9(1l) ,20(22) bisnorcholatetraene, and the like.

It is to be understood that the invention is not to be limited to the exact details of operation or exact compounds shown and described, as obvious modifications and equivalents will be apparent to one skilled in the art, and the invention is therefore to be limited only by the scope of the appended claims.

We claim:

1. A 3,22diacyloxy 5,7,9(11) ,20(22) bisnorcholatetraene wherein the acyloxy groups are of the formula AcO,' Ac being the residue of an unsubstituted organic monocarboxylic acid containing up to and including eight carbon atoms.

2. 3,22-diacetoxy 5,7,9(11) ,20(22) bisnorcholatetraene.

3. Process for the production of a 3,22-diacy1- 5. Process of claim 3, wherein the amine is dioxy-5,7,9(11),20(22) -bisnorcho1atetraene which methylaniline.

comprises heating a 5:8 maleic anhydride adduct 7 6. Process of claim 3, wherein the adduct is of said compound, in the presence of an organic an adduct of 3,22-diacetoXy-5,7,9(11) ,20(22) amine, at a temperature between about 100 and 5 bisnorcholatetraene.

225 degrees oentigrade, and separating the 322- ROBERT H. LEVIN. diacyloxy 5,7,9(11) ,20(22)- bisnorcholatetraene A VERN McINTOSH, JR. "from the reaction product. v GEORGE B. SPERO.

4. Process of claim 3, wherein the temperature is between about 175 and 200 degrees centigrade. 10 N0 references cited. 

1. A 3,22-DIACYLOXY-5,7,9(11),20(22) - BISNORCHOLATETRAENE WHEREIN THE ACYLOXY GROUPS ARE OF THE FORMULA ACO, AC BEING THE RESIDUE OF AN UNSUBSTITUTED ORGANIC MONOCARBOXYLIC ACID CONTAINING UP TO AND INCLUDING EIGHT CARBON ATOMS. 